BACKGROUND: Serotonin (5-hydroxytryptamine [5-HT]) was named for its isolation from blood serum (sero-) and ability to contract smooth muscle (-tonin). Thus, its relationship with the cardiovascular system began with its discovery.AIMS: This review will focus on the effects of 5-HT and its receptors in the vasculature, with a focus on their involvement in high blood pressure (hypertension). Two seemingly contradictory bodies of evidence exist that make it difficult to assign any one function to 5-HT in vascular control of blood pressure.RESULTS: In vitro, 5-HT is an established vasoconstrictor, the effects of which are amplified in hypertension. By contrast, 5-HT (or its precursor 5-hydroxytryptophan) lowers blood pressure when given chronically in vivo. We will discuss ideas that might help us understand these differences, discuss relatively new pharmacology parameters (e.g. biased, inverse agonism) as they pertain to 5-HT receptors, and pose questions that are vital to answer so as to understand the role played by 5-HT in control of blood pressure, especially as it pertains to vascular function.CONCLUSIONS: Our goal is to understand if the actions of 5-HT in hypertension are physiologically and clinically relevant. The community understands 5-HT has complex cardiovascular effects, and clinical studies have proven equivocal in terms of the involvement of 5-HT. This article provides a balanced view of evidence/literature that illustrates involvement of 5-HT in hypertension as controversial. It contributes new pharmacological knowledge of 5-HT compounds, and poses timely questions as to how this field can move forward. The take home message is that the cardiovascular effects of 5-HT are markedly complex such that we have not yet answered the question of whether 5-HT is beneficial or detrimental to hypertension.